Abstract

Pain is a key component of most rheumatologic diseases. In fibromyalgia, the importance
of central nervous system pain mechanisms (for example, loss of descending analgesic
activity and central sensitization) is well documented. A few studies have also noted
alterations in central pain processing in osteoarthritis, and some data, including
the observation of widespread pain sensitivity, suggest that central pain-processing
defects may alter the pain response in rheumatoid arthritis patients. When central
pain is identified, different classes of analgesics (for example, serotonin-norepinephrine
reuptake inhibitors, α2δ ligands) may be more effective than drugs that treat peripheral or nociceptive pain
(for example, nonsteroidal anti-inflammatory drugs and opioids).

Importance of chronic pain in the rheumatic diseases

Although pain is commonly the patients' utmost priority and the reason most patients
seek rheumatologic consultation, the medical community has historically had a poor
understanding of the etiology, mechanisms and treatment of pain. Rheumatologists often
consider pain a peripheral entity, but there is great discordance between pain severity
and purported peripheral causes of pain, such as inflammation and structural joint
damage (for example, cartilage degradation, erosions).

In recognition of the importance of pain in the rheumatic diseases, the American College
of Rheumatology Pain Management Task Force established an initiative to increase awareness
and call for organized research and education [1]. This initiative emphasizes the need for high-quality, quantitative research to understand
the mechanisms underlying individual differences in pain among patients with rheumatic
disease. Currently, most advances in the study of pain mechanisms have been in non-inflammatory
diseases, such as fibromyalgia [2]. These studies have highlighted the role of central pain-processing mechanisms, such
as loss of descending analgesic activity and central pain augmentation or sensitization.
Some pain researchers also believe that these mechanisms may have a significant impact
on pain severity among patients with osteoarthritis (OA) and rheumatoid arthritis
(RA), diseases that have historically been associated with peripheral pain due to
joint damage and inflammation.

In the present review we give a brief overview of the basic biology of acute and chronic
pain, including the role of central pain-processing defects. We discuss the role of
these mechanisms in diseases commonly seen in rheumatology practices (for example,
fibromyalgia, OA and RA) and consider potential treatments that may correct deficits
in central pain processing.

Basic biology of pain in healthy individuals

To determine the cause of pain, rheumatologists frequently categorize pain into acute
pain and chronic pain. Acute pain typically lasts from seconds to weeks or months.
Acute pain is often sudden in onset, as it is usually the direct result of a noxious
stimulus. In contrast, chronic pain is, by definition, present for at least 3 months.
Chronic pain may persist because the original inciting stimulus is still present and/or
because changes to the nervous system have occurred, making it more sensitive to pain.

Acute pain

Acute pain develops when a stimulus, such as pressure, heat or inflammation, is presented
to the body. Specialized receptors sense these stimuli and transport the signals to
the central nervous system (CNS) via nerve fibers that extend into the dorsal horn
of the spinal cord. The specialized receptors include low-threshold receptors that
respond to non-noxious levels of stimuli, and high-threshold receptors that sense
noxious stimuli (nociceptors). Both nerve fibers reside in soft tissue throughout
the body, including the muscle, skin and internal organs.

Two types of nociceptors, the Aδ afferent and the C afferent, are responsible for
the sensation and differentiation of mechanical, chemical and heat stimuli. The Aδ
nerve fiber has two classes, Type I and Type II, which respond to mechanical and heat
stimuli. Type I fibers have higher heat thresholds than Type II fibers, while Type
II fibers have higher mechanical thresholds than Type I fibers [3]. Consequently, the Type I Aδ afferents usually transmit noxious mechanical stimuli
while the Type II Aδ afferents often transmit noxious heat stimuli. The C nerve fibers
detect mechanical and heat stimuli, as well as chemical stimuli. Compared with pain
mediated by Aδ fibers, pain mediated by unmyelinated C fibers tends to be poorly localized
[4].

Chronic pain

Chronic pain is associated with many rheumatologic conditions, varying from non-inflammatory
syndromes, such as fibromyalgia, to systemic inflammatory diseases, such as RA. Depending
on the condition, as well as individual factors, differing pain mechanisms are involved.
Mechanisms of chronic pain can be divided into peripheral mechanisms and central mechanisms.

Peripheral pain mechanisms stem from abnormalities in the peripheral nerves, leading
to local areas of enhanced pain sensitivity. The most commonly cited peripheral pain
mechanism besides direct nociceptive input is peripheral sensitization, which probably
plays important roles in chronic pain mediated by OA and RA. This topic is covered
in depth by Schaible and colleagues in an earlier manuscript in this Biology of Pain
review series [5].

Central pain mechanisms operate at the level of the CNS, leading to enhanced widespread
pain sensitivity. Individuals with augmented central pain processing will display
diffuse hyperalgesia (increased pain in response to normally painful stimuli) and
allodynia (pain in response to normally nonpainful stimuli).

Abnormalities in central pain processing are divided into abnormalities in the descending
facilitatory and inhibitory pain pathways, and central sensitization (Figure 1). The descending pain pathways descend from the brainstem, hypothalamus and cortical
structures, and modulate sensory input from primary afferent fibers and projection
neurons in the dorsal horn of the spinal cord [6]. The best characterized descending analgesic path-ways are the serotonergic-noradrenergic
pathway and the opioidergic pathway. These pathways lead to the release of serotonin,
norepinephrine and endogenous opioids, which inhibit the release of excitatory neurotransmitters
such as glutamate. These pathways are activated in response to noxious stimuli, leading
to a widespread decrease in pain sensitivity after exposure to an acutely painful
stimulus. In chronic pain syndromes, descending analgesic activity is often impaired
or absent - hence the term loss of descending analgesia.

Figure 1.Descending pain pathways and central sensitization. Descending pain pathways and central sensitization modulate the pain response in
the dorsal horn of the spinal cord. Descending analgesic pathways include the serotonin-norepinephrine
and opioidergic descending pathways, which dampen pain sensitivity response. Loss
of descending analgesia leads to hyperalgesia and allodynia. Central sensitization
occurs through the action of glutamate on the N-methyl-D-aspartate (NMDA) receptor, resulting in an increase in intracellular calcium levels
and kinase activation, leading to hyperalgesia and allodynia.

In the present review, loss of descending analgesia is used synonymously with the
term loss of diffuse noxious inhibitory controls. Experimentally, diffuse noxious
inhibitory control is commonly assessed by exposing subjects to two types of stimuli:
the conditioning stimulus, and the test stimulus. The conditioning stimulus is an
acute noxious stimulus that activates descending analgesic pathways, leading to a
diffuse decrease in pain sensitivity throughout the body [7]. In healthy controls, a wide range of noxious stimuli - including ice-cold water,
contact heat and tourniquet ischemia - are all effective conditioning stimuli, producing
increased pain thresh-olds throughout the body [7]. The test stimulus is a painful stimulus that is applied at baseline and during/after
exposure to the conditioning stimulus. The magnitude of the descending analgesic response
is the difference between the pain rating of the test stimulus before exposure to
the conditioning stimulus and the pain rating of the test stimulus after exposure
to the conditioning stimulus [7].

When evaluating these studies, it is important to understand that, although commonly
used to assess descending analgesia, these studies do not specifically localize the
areas of pain modulation to the descending spinal tracts. Changes in pain threshold
after noxious pain stimulation may also partly reflect changes in attention (for example,
distraction) or other processes that influence pain perception. To directly assess
the descending spinal pathways, electrophysiologic assessments of the spinal nociceptive
flexion reflex must be performed.

While descending analgesic pathways are typically tonically active and inhibit the
upward transmission of pain signals, other descending pain-processing mechanisms involve
enhanced activity down the descending facilitatory pain pathways that lead to generalized
increases in sensory sensitivity [8]. The role of these facilitatory pathways, however, has not been well established
in human studies.

In addition to descending inhibitory and facilitatory pathways, central sensitization
also leads to enhanced CNS neuron excitability and increased transmission of pain
signals. In the literature, the term central sensitization may be used in two ways:
to describe general abnormalities in central pain processing (which, in the present
review, we will refer to as central augmentation); and to describe a specific defect
in central pain processing associated with activation of N-methyl-D-aspartate (NMDA) receptor channels (which we will refer to as central sensitization).

Central sensitization occurs largely as a result of enhanced release of glutamate
and substance P at the level of the spinal cord. Glutamate is the major excitatory
neurotransmitter in the nervous system, and it acts on three receptor subsets: the
α-amino-3-hydroxy-5-methyl-4-isoxazeloproprionic acid receptor, the NMDA receptor
and the G-protein-coupled metabotropic family of receptors. While the α-amino-3-hydroxy-5-methyl-4-isoxazeloproprionic
acid receptor is responsible for the baseline response to noxious stimuli, the NMDA
receptor enhances and extends the pain response [9]. NMDA receptor activation results in calcium influx, stimulating calcium/calmodulin-dependent
kinases and extracellular signal-regulated kinases. These changes modulate CNS plasticity,
resulting in the hyperalgesia and allodynia that characterize central sensitization
[9].

Experimentally, central sensitization is characterized by di use pain sensitivity
and increased pain severity during and after repeated stimuli. Individuals with central
sensitization have low thermal and mechanical thresholds in a diffuse pattern, reflecting
enlargement of the spinal cord neuron receptive fields [4]. Repeated stimulation results in painful after-sensations that persist after a stimulus
is withdrawn; and results in enhanced temporal summation of pain such that the pain
rating for the last stimulus is higher than the pain rating for the first stimulus,
even though the stimuli are exactly the same. NMDA receptor antagonists, such as dextromethorphan
and ketamine, inhibit temporal summation [10-12].

Studies suggest that maintenance of central augmentation requires persistent noxious
peripheral input, even in syndromes such as fibromyalgia, which is characterized by
the absence of well-defined, localized, pain-causing lesions [13,14]. A recent study of 68 fibromyalgia patients with myofascial pain syndromes and 56
fibromyalgia patients with regional joint pain showed that peripheral trigger point
injections and hydroelectrophoresis ameliorate fibromyalgia pain and increase pain
thresholds at sites distant from the therapeutic interventions [15], providing further evidence that painful peripheral stimuli contribute to the perpetuation
of central augmentation.

Fibromyalgia

Fibromyalgia is the prototypical non-inflammatory chronic pain syndrome. The disease
is characterized by chronic widespread pain and associated symptoms, including sleep
problems, fatigue, cognitive dysfunction and depression. Quantitative sensory testing
methods have consistently identified abnormalities in pain perception among fibromyalgia
patients (Table 1). Most notably, patients with fibromyalgia have diffusely lower pressure pain thresholds
than healthy controls [16]. This diffuse hyperalgesic state of central augmentation of pain processing has been
repeatedly identified using functional neuroimaging techniques [17,18] and may partly be due to specific defects such as loss of descending analgesic activity
and central sensitization.

Evidence for the role of defects in descending analgesic activity in fibromyalgia
comes from studies of conditioned pain modulation [19-21]. In a study of 26 healthy controls and 25 fibromyalgia patients, heat stimulation
of the foot increased pain thresholds to electric stimulation of the forearm among
healthy controls but not among fibromyalgia patients [19]. Similarly, tourniquet ischemic pain increased pressure pain threshold in 10 healthy
controls but not in 10 fibromyalgia patients [20], and a noxious cold stimulus reduced heat pain ratings among 20 healthy controls
but not among 45 fibromyalgia patients [21].

These defects in inhibitory pain responses may be due to blunted activity of the descending
serotonergic-noradrenergic system. Fibromyalgia patients have reduced serum levels
of serotonin and its precursor, L-tryptophan, as well as reduced levels of the principal serotonin metabolite, 5-hydroxyindoleacetic
acid, in their cerebral spinal fluid [22]. Levels of 3-methoxy-4-hydroxyphen-ethylene, the principal metabolite of norepinephrine,
are also lower in the cerebral spinal fluid of fibromyalgia patients compared with
healthy controls [22]. In contrast, biochemical and imaging findings suggest that fibromyalgia patients
actually have increased activity of endogenous opioidergic systems, which is consistent with anecdotal experience
that opioids are ineffective analgesics in patients with fibromyalgia and related
conditions [23,24].

The evidence for central sensitization in fibromyalgia predominantly consists of studies
comparing the magnitude of temporal summation in fibromyalgia patients with healthy
controls. Although both fibromyalgia patients and healthy controls experience temporal
summation, the magnitude of temporal summation may be slightly greater in fibromyalgia
patients [25]. The magnitude of temporal summation is decreased by treatment with either fentanyl
injections or ketamine, an NMDA antagonist [10,12].

In addition to heightened sensitivity to pain, fibromyalgia patients are also more
sensitive to a variety of other sensory stimuli [26,27]. This polysensory augmentation may partly be due to enhanced neural activity that
has been consistently observed in brain regions such as the insula, a region known
to code for the intensity of all sensory information [17]. Previous studies suggest that the anterior insula is involved in the affective/emotional
modulation of pain processing, while the posterior insula is involved in the sensory/discriminative
processing of pain [28]. Compared with controls, fibromyalgia patients have higher levels of glutamate in
the posterior insula, and changes in glutamate levels in the posterior insula are
correlated with changes in pain and tenderness after acupuncture [29,30]. These studies suggest that at least a component of pain in fibromyalgia is a result
of sensory amplification, rather than just affective processing.

Genetic studies also support an association between the serotonergic-noradrenergic
system and fibromyalgia. In candidate gene studies, polymorphisms in the metabolism
and transport of monoamines (for example, catecholamine-o-methyltransferase, serotonin 5-hydroxytryp-tamine type 2a receptor, serotonin transporter)
have been associated with the diagnosis or severity of fibromyalgia [31-35]. Most of these studies were small, however, and conflicting data exist - with some
studies reporting no association between these genes and fibromyalgia [31,36-38]. Future studies, incorporating a larger number of fibromyalgia patients and/or utilizing
meta-analysis techniques, are needed.

In addition to genetic studies, a recent surge of interest has surrounded the use
of functional magnetic resonance imaging (fMRI) to study pain in a more quantitative,
objective manner. This area of research, however, is still relatively new. As such,
we present the following results as preliminary evidence for the role of the CNS in
pain modulation, rather than as well-established facts.

Cook and colleagues noted similar findings in a study examining responses to heat
stimuli [39]. In addition, their study reported post hoc analyses showing no neural activation in the periaqueductal gray region of fibromyalgia
patients exposed to painful heat stimuli but significant activity in the periaqueductal
gray region of healthy controls exposed to painful heat stimuli. Because previous
studies have suggested that the periaqueductal gray region is involved in descending
pain modulation, these findings were interpreted as possible evidence for loss of
descending analgesia among fibromyalgia patients. A more recent article by Jensen
and colleagues showed similar decreases in neuronal activation in the anterior cingulate
cortex, a region also involved in pain modulation [40].

The fMRI techniques examining resting-state functional connectivity have also identified
the default mode network as a potential modulator of spontaneous clinical pain in
fibromyalgia patients. The default mode network consists of neural regions (medial
frontal gyri, hippocampus, lateral temporal cortex, posterior cingulate cortex, precuneus,
inferior parietal lobe) that are active at rest and may be involved in self-referential
thought. In a study of 18 fibromyalgia patients and 18 age-matched and sex-matched
controls, Napadow and colleagues noted that connectivity between the default mode
network and the insula was positively correlated with clinical pain severity [41].

Osteoarthritis

OA is a common degenerative joint disease, characterized by damage to cartilage and
bone, which affects approximately 27 million people in the United States [42]. Individuals with OA often suffer from chronic pain, ultimately leading to significant
disability and healthcare costs. Despite the significant impact of pain in OA patients,
little is known about the causes of the pain associated with OA.

On a population level, pain intensity (via patient self-report) correlates poorly
with peripheral joint damage assessed by the Kellgren-Lawrence radiologic classification
criteria [43]. Within individuals, however, pain severity is strongly associated with radiographic
damage [44]. Taken together, these studies suggest that other mechanisms of pain that are not
knee specific (for example, enhanced pain sensitivity due to alterations in central
pain processing) may play a role in the variability in pain severity across individuals.

Studies utilizing quantitative sensory testing indicate that OA patients are more
sensitive to experimental pain stimuli than healthy controls (Table 1). Most studies have focused on pain sensitivity at sites close to affected joints,
showing that OA patients have lower mechanical and thermal pain thresholds (for example,
higher pain sensitivity) than healthy controls [45-49]. Intriguingly, O'Driscoll and Jayson also reported low-pressure pain thresholds at
the forehead, a clinically nonpainful site, unaffected by OA [50]. Similarly, among 15 patients with OA of the hip, Kosek and Ordeberg noted increased
sensitivity to pressure, ischemia and innocuous warm stimuli at the affected hip and
at the contralateral hip, indicating a diffuse process extending beyond just the affected
joint. These studies suggest that OA pain, historically considered a peripheral entity,
may also be modulated via widespread mechanisms controlled by the CNS.

Assessments of the widespread nature of pain sensitivity in OA have provided further
support for the role of central pain mechanisms in OA. Bajaj and colleagues infused
hypertonic saline into the tibialis anterior muscles of 14 OA patients and of 14 age-matched
and sex-matched controls. OA patients reported increased pain intensity and larger
pain areas, extending to the toes, whereas healthy controls reported lower pain intensity
with the distribution of pain ending near the ankle. The authors attributed these
findings to changes in central pain mechanisms [51]. In a larger study of 62 female knee OA patients and 22 age-matched healthy controls,
Imamura and colleagues highlighted the widespread distribution of pain sensitivity,
showing subcutaneous hyperalgesia to pressure stimuli at seven dermatome levels, myotomal
hyperalgesia at nine lower extremity muscle groups, and sclerotomal hyperalgesia at
eight sites across the lower back and legs. The authors speculated that both peripheral
and central mechanisms contribute to the chronic pain state, with peripheral mechanisms
being more important in the early stages, and central mechanisms dominating in the
later stages [52].

Additional evidence for defects in central pain processing comes from studies assessing
specific pain-processing mechanisms, such as loss of descending analgesic activity.
In a study of 48 knee OA patients and 24 age-matched and sex-matched controls, OA
patients exhibited greater loss of descending analgesic activity than healthy controls
[49] - a finding similar to the previous study by Kosek and Ordeberg of 15 hip OA patients
[47]. The study by Kosek and Ordeberg was particularly interesting because it showed that
loss of descending analgesic activity is contingent upon the chronic pain state and
that loss of descending analgesic activity can be reversed [47]. After the initial evaluation, 13 out of 15 hip OA patients underwent surgery, resulting
in significant clinical pain relief. When the patients were reassessed 6 to 14 months
after surgery (when pain-free), they exhibited significant increases in pain thresholds
compared with pre surgery. Postsurgery pain thresholds were similar to pain thresholds
among healthy controls. Furthermore, modulation of pain through descending analgesic
pathways was restored. These results suggest that dysfunctional central pain mechanisms
are associated with the chronic pain state, and removal of the inciting pain stimulus
may lead to normalization of central pain processing [47].

In addition to loss of descending analgesic activity, central sensitization may also
alter pain processing among OA patients. In a study examining the effects of repeated
pressure stimulation on pain sensitivity, temporal summation at the knee and tibialis
anterior muscle was significantly greater among patients with knee OA compared with
controls [49].

Studies utilizing fMRI during quantitative sensory testing have also shown enhanced
activity in the periaqueductal gray matter of OA patients compared with healthy controls
[48]. This finding was interpreted as an increase in activity of the descending facilitatory
path-ways, a mechanism that would have the same net effect as a decrease in descending
analgesic activity. Notably, this finding is the opposite of that found by Cook and
colleagues in fibromyalgia patients [39]. Cook and colleagues reported lower levels of activity in the periaqueductal gray
matter of fibromyalgia patients compared with pain-free controls, which the authors
interpreted as an impairment in descending analgesic pathways. Other studies using
fMRI have suggested that OA-related knee pain is modulated by the medial pain system,
a network of brain structures associated with the affective dimension of pain processing
[53].

Rheumatoid arthritis

In contrast to fibromyalgia and OA, RA is characterized by systemic inflammation.
Although inflammation contributes to pain in RA, it may not be the only factor. For
some patients, pain does not improve despite treatment with anti-inflammatory disease-modifying
anti-rheumatic drugs. In a cross-sectional analysis of 12,090 RA patients recruited
from rheumatology practices, pain levels were almost constant over RA duration, even
though most participants were treated with a disease-modifying anti-rheumatic drug,
an anti-TNF agent or both [54]. A large longitudinal study, consisting of 882 RA patients, reported that pain initially
decreased during the first 3 years after diagnosis but subsequently increased over
time. The authors speculated that the initial decrease in pain was due to control
of inflammation while the later rise in pain was attributed to other pain pathways
[55].

Although few studies have specifically examined the role of central pain-processing
mechanisms in RA, studies utilizing dolorimetry to assess pain thresholds suggest
that these other pathways may include deficits in central pain processing. Deficits
in central pain processing are characterized by enhanced pain sensitivity in a widespread
distribution, and studies have consistently shown that RA patients have lower pressure
pain thresholds (higher pain sensitivity) than healthy controls at joint and nonjoint
sites [56-58].

Only one study has directly examined the role of descending analgesic activity in
RA patients [59]. The study compared the magnitude of descending analgesic activity in 11 patients
with RA of short duration to 11 healthy controls and in 10 patients with RA of long
duration to 10 healthy controls. The magnitude of descending analgesic activity in
both groups of RA patients was less than the magnitude of descending analgesic activity
in healthy controls. These differences were not statistically significant [59], but given the small samples sizes it was difficult to determine whether there really
was no difference between the two groups or whether the study was underpowered to
detect an effect.

A few small studies have provided support for the role of central sensitization in
pain augmentation among RA patients. Wendler and colleagues demonstrated using electroencephalography
that, compared with age-matched and sex-matched controls, RA patients had enhanced
cortical responses to repeated noxious stimulation, suggesting changes in CNS modulation
of pain [60]. Morris and colleagues showed that capsaicin induces a larger area of hyperalgesia
among RA patients compared with healthy controls [61]. This area of enhanced hyperalgesia may correspond to the enlargement of spinal cord
neuron receptive fields, characteristic of central sensitization.

The relationships between inflammation, psychosocial factors and peripheral and central
pain processing are intricately entwined. In a recent study of 59 female RA patients,
we showed that C-reactive protein levels were inversely associated with pain thresholds
at joint sites but not nonjoint sites, consistent with peripheral sensitization [65]. Sleep disturbance, on the other hand, was associated with pain thresholds at both
joint and nonjoint sites, indicating a central mechanism linking pain sensitivity
and sleep problems. Recent studies in healthy women [66] and in patients with temperomandibular joint disorder [67] support this hypothesis, showing that short sleep duration and forced awakenings
are associated with loss of descending analgesic activity.

Mechanism-based treatment

The rheumatologist's approach to pain management has historically focused on treatment
of the underlying disease process. With recent advances in the study of pain mechanisms,
it has become clear that pain is multifactorial in origin, and successful treatment
may require a combination of medications with different mechanisms of action. Although
most rheumatologists are familiar with the use of nonsteroidal anti-inflammatory drugs
for pain, few are experienced with newer classes of medications, such as antidepressants
and anti-convulsants, that target central pain-processing mechanisms. Current treatments
for central pain have mainly been used in the fibromyalgia population, although a
few studies have examined these agents in OA patients and RA patients. In the remainder
of the present review we give an overview of the medications that are likely to play
an increasing role in pain management among patients with rheumatic disease.

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) work by inhibiting serotonin and norepinephrine reuptake.
The most commonly used TCA is amitriptyline. Other TCAs include dothiepin and imipramine.

Ten randomized, double-blinded, placebo-controlled trials have examined the efficacy
of amitriptyline in fibromyalgia [68]. A meta-analysis of these studies revealed poor to moderate evidence for the efficacy
of amitriptyline 25 mg daily over 6 to 8 weeks but no evidence for the efficacy of
amitriptyline at higher doses or longer treatment durations. Outcome measures included
patient and physician global assessment of disease, the visual analog pain scale and
the tender point count [68]. Although these studies were classified as of high methodological quality by Jadad's
score, other quality issues (for example, sample size, duration of follow-up and retention
rates) were not considered and may limit the strength of these results.

Studies of TCAs in OA and RA have been limited. To our knowledge, no studies have
specifically assessed the role of TCAs in the treatment of pain in OA - although one
study examined the efficacy of imipramine in the treatment of pain in a mixed population
of 66 OA, RA and ankylosing spondylitis patients, showing significant pain relief
in patients treated with imipramine compared with placebo [69]. In RA, four out of six studies reported significant improvements in pain among RA
patients taking TCAs compared with RA patients on placebo [70-73]. The largest study, including 184 RA patients, showed a decrease in pain among patients
treated with dothiepin, but the change in pain scores was not statistically different
from the change in pain scores among patients treated with placebo [74]. Studies examining the effects of TCAs on depression and pain showed that improvements
in pain were independent of improvements in depression [70,73].

In clinical practice, the use of TCAs is often problematic because TCAs are associated
with substantial adverse effects, and compliance with these medications is low. In
addition to inhibiting serotonin and norepinephrine reuptake, TCAs also block cholinergic,
histaminic and α-adrenergic receptors. As a result, many patients taking TCAs experience
side effects such as sedation, dizziness, blurred vision, constipation and dry mouth.
Dry mouth is particularly problematic in the RA population because many patients also
have secondary Sjogren's syndrome, an inflammatory disorder characterized by decreased
salivary gland function.

Serotonin norepinephrine reuptake inhibitors

Serotonin norepinephrine reuptake inhibitors (SNRIs) have similar noradrenergic/serotonergic
reuptake ratios compared with TCAs. While TCAs have many effects other than inhibiting
serotonin and norepinephrine reuptake, however, SNRIs are selective. A selective SNRI,
such as duloxetine or milnacipran, could thus show greater overall benefit by enhancing
the serotonergic and noradrenergic effects that lead to drug efficacy, while minimizing
the dose-limiting effects of toxicity.

SNRIs modulate the descending serotonin-norepinephrine pathways involved in central
pain-inhibiting mechanisms and are effective in the treatment of conditions characterized
by defects in central pain processing (for example, fibromyalgia). In a group of 40
healthy individuals with low descending analgesic activity at baseline, treatment
with duloxetine 60 mg daily resulted in an increase in descending analgesic activity
from 0.15 to 19.35 within 1 week [75].

Two SNRIs, duloxetine and milnacipran, are approved by the Food and Drug Administration
for the treatment of fibromyalgia. In three large, randomized placebo-controlled trials
of fibromyalgia patients, duloxetine was associated with significant improvements
in clinical pain [76-78]. Similar results have been reported in studies examining the effects of milnacipran
on fibromyalgia pain [79-81]. The pain-relieving effects of these agents have been observed in depressed patients
and in non-depressed patients [79].

Recent studies have expanded the potential use of SNRIs to other chronic painful conditions,
including OA. In a 13-week, randomized, double-blind, placebo-controlled trial of
231 patients with knee OA, duloxetine 60 to 120 mg daily significantly reduced mean
24-hour pain scores [82]. Duloxetine was also associated with significant improvements in the Western Ontario
and McMasters physical function scores. To date, no studies have examined the effect
of SNRIs on pain in RA.

The α2δ ligands

The α2δ ligands, pregabalin and gabapentin, are anticonvulsants used to treat chronic pain
conditions such as postherpetic neuralgia and diabetic neuropathy. Pregabalin and
gabapentin bind to the α2δ subunit of calcium channels, inhibiting the release of neurotransmitters, including
glutamate, noradrenaline, serotonin, and substance P. These compounds could thus work
in individuals with central sensitization, as well as decreased descending analgesic
response due to low serotonergic-noradrenergic activity.

Among fibromyalgia patients, pregabalin has consistently been associated with improvements
in pain severity [83,84]. A Cochrane systematic review including 1,376 fibromyalgia patients treated with
pregabalin 300 to 450 mg daily reported a relative benefit between 1.5 (95% confidence
interval 1.2 to 1.9) and 1.7 (95% confidence interval 1.4 to 2.1) for a 50% decrease
in pain [85]. The authors concluded that although some patients will experience moderate pain
relief from pregabalin, few will experience a large effect [85]. No studies have examined the effect of pregabalin on pain in OA or RA patients,
although a recent animal study suggested that pregabalin decreased pain sensitivity
in a rat model of OA [86].

Conclusions

Central pain mechanisms play important roles in wide-spread pain syndromes, including
fibromyalgia. The role of these mechanisms in rheumatologic diseases such as OA and
RA is not well understood. A few small studies, utilizing quantitative sensory testing
and fMRI, have documented loss of descending analgesic activity and alterations in
CNS activity among OA patients, and a couple of small studies suggest a role for central
sensitization in RA (Table 1). The data regarding loss of descending analgesic activity in RA, however, remain
inconclusive.

Larger studies involving extensive pain phenotyping and comprehensive information
about disease characteristics are necessary to better understand the impact of central
pain mechanisms in OA and RA. Studies are also necessary to determine whether these
patients, or a sub-group of these patients, may benefit from treatment with drugs
such as SNRIs and α2δ ligands that target central pain mechanisms. If central pain mechanisms do play
a significant role in pain processing among OA and RA patients, these medications
may be attractive adjunctive treatments to manage pain in patients with rheumato-logic
disease.

Competing interests

YCL receives grant support from Forest Laboratories and holds stocks in Merck and
Company, Inc., Novartis, and Elan Corporation. DJC has acted as a consultant for Pfizer,
Lilly, Forest Laboratories, Cypress Biosciences, Pierre Fabre, UCB, Johnson and Johnson,
Nuvo, Merck and Company, Inc. and Wyeth. DJC has also received grant support from
Pfizer, Cypress Bioscience, and Forest. NJN declares that he has no competing interests.

Note

This article is part of the series Evolving understanding of the biology of pain and
its application to patient care, edited by Daniel Clauw and Anthony Jones. Other articles
in this series can be found at http://arthritis-research.com/series/painwebcite

Acknowledgements

Grant support was received from NIH/NIAMS grant AR057578. The funding body played
no role in the study design; in the collection, analysis, and interpretation of data;
in the writing of the manuscript; and in the decision to submit the manuscript for
publication.